Computational Modeling and Accelerated Aging of the Ascending Aorta

升主动脉的计算模型和加速老化

• 批准号: 8489053
• 负责人: Jay D. Humphrey
• 金额: $ 7.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489053
• 关键词: Accounting; Aging; Aging-Related Process; Aneurysm; Aorta; Area; Arteries; Biomechanics; Blood Pressure; Blood flow; Cardiac; Cardiovascular system; Cell Lineage; Central Artery; Cessation of life; Child; Code; Collagen; Complement; Complex; Computer Simulation; Coupled; Custom; Data; Development; Disease; Dissection; Elastic Fiber; Elements; Equilibrium; Excision; Extracellular Matrix; FBN1; Feasibility Studies; Fibrillar Collagen; Genes; Genetic; Glycosaminoglycans; Goals; Growth Factor Receptors; Health; Heart; Homeostasis; Human; In Vitro; Kidney Diseases; Knockout Mice; Lead; Left Ventricular Function; Length; Measurement; Measures; Mechanics; Modeling; Muscle function; Mutation; Myocardial Infarction; Neural Crest; Normalcy; Operative Surgical Procedures; Physiologic pulse; Pilot Projects; Plant Roots; Production; Property; Proteoglycan; Pulse Pressure; Reporting; Research; Research Methodology; Residual state; Resource Sharing; Risk; Risk Factors; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Stress; Stroke; Structure; Swelling; Syndrome; Technology; Testing; Thick; Thoracic Aortic Aneurysm; Thoracic aorta; Time; Torsion; Transforming Growth Factors; Ultrasonography; Variant; Ventricular Function; age related; alpha Actin; arterial stiffness; ascending aorta; base; beta-Myosin; cerebrovascular; design; disability; experience; fibulin; hemodynamics; heritable connective tissue disorder; improved; insight; kidney vascular structure; next generation; novel; open source; pressure; public health relevance; research and development; validation studies; young adult

DESCRIPTION (provided by applicant): The ascending aorta experiences unique multiaxial loading during each cardiac cycle: finite distension due to changes in blood pressure plus finite extension, torsion, and bending due to the direct action of the beating heart. We hypothesize that this unique, cyclic multiaxial loading coupled with the unique underlying micro- structure and cell lineage of the ascending aorta accelerates a mechano-aging process that manifests as the recently reported earliest reductions in distensibility and wall strain and the earliest and mot dramatic increases in length of any segment of the human aorta. We hypothesize further that heritable connective tissue disorders that commonly lead to aneurysms of, and dissections in, the aortic root or ascending aorta also tend to manifest first in this region of the aorta because they accelerate this mechano-aging process. A singularly important histopathological feature of this aging process is an increased accumulation, and at times pooling, of glycosaminoglycans, the mechanical implications of which have never been studied. The two goals of this R03 application are: (1) Build a next generation computational (finite element) mixture model of the ascending aorta that embodies the unique biomechanics: multiaxial loading, regionally varying residual stresses and nonlinear material properties that off-set regional variations in geometry to give rise to mechanical homeostasis in normalcy, and pre-mature alterations in elastic fibers, smooth muscle, fibrillar collagens, and most importantly glycosaminoglycans (via a Donnan swelling pressure); and (2) Inform and validate the finite element model using data from wild-type and fibulin 5 null mice. Data will include microCT information on the overall geometry, ultrasound information on local blood flow, nonlinear material properties measured using custom in vitro biaxial testing, residual stress related measurements of opening angles, and histo-morphological measures of regional wall thicknesses and composition. This proposal is submitted under the R03 mechanism for it focuses primarily on the "development of research methodology" (i.e., a nonlinear constrained mixture constitutive relation for the ascending aorta that accounts for the first time for progressive losses of elastic fiber integrity, pooling of GAGs PGs, and remodeling of collagen that results in accelerated aging), the "development of new research technology" (i.e., the first open source finite element model capable of modeling the unique evolving histo-mechanics of the ascending aorta), and "pilot or feasibility studies" (i.e., initial validation studies using fibulin 5 null mice, which show accelerated aging). We submit that development of the proposed, next generation computational model of the ascending aorta will enable much more realistic studies by ourselves and (via resource sharing) others to elucidate underlying biomechanical causes of thoracic aortic aneurysms and dissections, diminished left ventricular function due to stiffening of the aorta, and deleterious systemic hemodynamics as well as an improved design of surgical procedures or grafts.

描述(申请人提供)：升主动脉在每个心动周期中经历独特的多轴负荷：由于血压变化而产生的有限扩张，以及由于心脏跳动的直接作用而产生的有限伸展、扭转和弯曲。我们推测，这种独特的循环多轴负荷加上升主动脉独特的基础微结构和细胞谱系，加速了机械老化过程，表现为最近报道的最早的扩张性和管壁应变的减少，以及人类主动脉任何节段最早和最不显著的长度增加。我们进一步假设，通常导致主动脉根部或升主动脉的动脉瘤和夹层的遗传性结缔组织疾病也往往首先出现在主动脉的这一区域，因为它们加速了这一机械老化过程。这种老化过程的一个非常重要的组织病理学特征是糖胺多聚糖的积累增加，有时甚至聚集在一起，其力学意义从未被研究过。R03应用程序的两个目标是：(1)建立下一代计算(有限元)升主动脉混合模型，该模型体现了独特的生物力学：多轴加载、区域变化的残余应力和非线性材料属性，抵消了几何上的区域变化 (2)使用野生型和fiblin 5基因缺失小鼠的数据，在正常情况下引起机械动态平衡，以及弹性纤维、平滑肌、纤维胶原和最重要的糖胺聚糖(通过Donnan肿胀压力)的早熟改变；以及(2)告知和验证有限元模型。数据将包括有关整体几何结构的MicroCT信息、关于局部血流的超声信息、使用定制体外双轴测试测量的非线性材料特性、与残余应力相关的张开角测量，以及局部壁厚和成分的组织形态测量。本提案是在R03机制下提交的，因为它主要侧重于“研究方法的发展”(即，升主动脉的非线性约束混合物本构关系，首次解释了弹性纤维完整性的进行性丧失、GAG PG的聚集以及导致加速老化的胶原重塑)、“新研究技术的发展”(即，第一个能够模拟升主动脉独特演变的组织力学的开放源码有限元模型)，以及“初步或可行性研究”(即，使用fibuin 5基因空白小鼠的初步验证研究，这表明衰老加速)。我们提出， 拟议的下一代升主动脉计算模型的开发将使我们和其他人(通过资源共享)能够进行更现实的研究，以阐明胸主动脉瘤和夹层的潜在生物力学原因、由于主动脉硬化而导致的左心功能下降、有害的全身血流动力学以及外科手术或移植物的改进设计。